SCOPE-based target and pathway enrichment identifies the histamine H1 receptor as a regulator of exodosis
- 1Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health
- 2Cellular Stress and Inflammation Section, National Institute on Drug Abuse, National Institutes of Health
Abstract
Introduction: Phenotypic screening enables discovery of small molecules without requiring predefined targets, but mechanistic interpretation remains challenging due to polypharmacology and pathway complexity.
Methods: We developed SCOPE (Screening Compound Ontology for Pathway Enrichment), a KNIME-based computational framework that links compound-level screening data to annotated targets and pathways to facilitate generation of mechanistic hypotheses. SCOPE integrates multi-source target annotations and performs sequential target- and pathway-level statistical enrichment using the screened compound library as the background to prioritize shared mechanisms of action.
Results: Applied to a previously established high-throughput screen for modulators of endoplasmic reticulum (ER)-stress induced secretion of ER resident proteins, a process known as exodosis, SCOPE identified calcium signaling as the most enriched KEGG pathway without prior biological context. Its target enrichment revealed several G protein-coupled receptors (GPCRs) linked to inositol 1,4,5-trisphosphate receptors (IP3Rs)-mediated calcium signaling, with widespread antagonism of these receptors among compounds that reduced exodosis, implicating this pathway in the regulation of exodosis. Notably, SCOPE uncovered a novel role for the histamine receptor HRH1 in exodosis, which was validated by RNAi knockdown, gene knockout, and pharmacological modulation, implicating HRH1 as a potential therapeutic target for modulating exodosis.
Discussion: These results highlight SCOPE’s potential to prioritize experimentally testable targets and pathways from phenotypic screening data.
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BibTeX
@article{kapoor2026scopebased,
title = {{SCOPE-based target and pathway enrichment identifies the histamine H1 receptor as a regulator of exodosis}},
author = {Abhijeet Kapoor and Keith J. Kelleher and Suzanne M. Underhill and Sankalp Jain and Darian Williams and Brandon K. Harvey and Mark J. Henderson},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1972662},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1972662/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SCOPE-based target and pathway enrichment identifies the histamine H1 receptor as a regulator of exodosis
AU - Abhijeet Kapoor
AU - Keith J. Kelleher
AU - Suzanne M. Underhill
AU - Sankalp Jain
AU - Darian Williams
AU - Brandon K. Harvey
AU - Mark J. Henderson
PY - 2026
DA - 2026/10/19
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1972662
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1972662/full
AB - Introduction: Phenotypic screening enables discovery of small molecules without requiring predefined targets, but mechanistic interpretation remains challenging due to polypharmacology and pathway complexity. Methods: We developed SCOPE (Screening Compound Ontology for Pathway Enrichment), a KNIME-based computational framework that links compound-level screening data to annotated targets and pathways to facilitate generation of mechanistic hypotheses. SCOPE integrates multi-source target annotations and performs sequential target- and pathway-level statistical enrichment using the screened compound library as the background to prioritize shared mechanisms of action. Results: Applied to a previously established high-throughput screen for modulators of endoplasmic reticulum (ER)-stress induced secretion of ER resident proteins, a process known as exodosis, SCOPE identified calcium signaling as the most enriched KEGG pathway without prior biological context. Its target enrichment revealed several G protein-coupled receptors (GPCRs) linked to inositol 1,4,5-trisphosphate receptors (IP3Rs)-mediated calcium signaling, with widespread antagonism of these receptors among compounds that reduced exodosis, implicating this pathway in the regulation of exodosis. Notably, SCOPE uncovered a novel role for the histamine receptor HRH1 in exodosis, which was validated by RNAi knockdown, gene knockout, and pharmacological modulation, implicating HRH1 as a potential therapeutic target for modulating exodosis. Discussion: These results highlight SCOPE’s potential to prioritize experimentally testable targets and pathways from phenotypic screening data.
SN - 1663-9812
ER -